1. Field of the Invention
The present invention relates generally to the field of pharmacology and cancer treatment. Specifically, the present invention provides formulations and methods for small particle aerosol delivery by inhalation of aqueous dispersions of liposomes carrying anti-cancer drugs to the respiratory tract.
2. Description of the Related Art
Small particle liposome aerosol treatment consists of lipid-soluble or water-soluble anti-cancer drugs incorporated into liposomes, which are administered from aqueous dispersions in a jet nebulizer (see U.S. Pat. No. 5,049,388). Aerosols of 1-3 .mu.m mass median aerodynamic diameter, generated upon nebulization, enable targeted delivery onto surfaces of the respiratory tract. The deposited liposomes subsequently release drug locally within the lung or into the blood circulation with delivery to extra-pulmonary tissue. If the drug is lipid soluble, it will associate with the lipid molecules in a manner specific to the lipid employed, the anti-cancer drug employed and possibly it may be modified further by various soluble constituents which may be included in the suspending aqueous medium. Such soluble constituents may include buffering salts and possibly inositol to enhance the synthesis and secretion of surfactant phospholipid in lung tissue and to minimize respiratory distress already present or that which might result from the aerosol treatment (Hallman, M., et al. Inositol Supplementation in Premature Infants with Respiratory Distress Syndrome, N. Eng. J. Med. 1992 326:1233-1239).
If the drug is water soluble, it may be incorporated by appropriate procedures in aqueous vesicles that exist in concentric spaces between lipid bilayers (lamellae) of the multilamellar liposome. Unilamellar liposomes may be prepared; however, their capacity to entrap either lipid-soluble or water-soluble drugs is diminished since entrapment is restricted to one central vesicle. Additionally, lipid complexes of various sizes can be used.
Nebulization shears liposomes and other lipid complexes to sizes readily discharged from the nozzle of the nebulizer. Liposomes and other lipid complexes up to several microns in diameter are typically sheared to diameters of less than 500 nm, and may be considerably smaller than that depending on the operating characteristics of the nebulizer and other variables. Shearing of water-soluble drugs contained in liposomes or complexes will release appreciable amounts of the water soluble compound, perhaps 50 percent. This is not a contraindication to their use, but it means that two forms of the drug preparation is administered, and the effect includes the therapeutic effect that would be produced by both forms if either form had been given alone. Many other details of liposome aerosol treatment are described in U.S. Pat. No. 5,049,388. Moreover, it is also possible to incorporate more than one drug in a aerosol liposome treatment, either by mixing different drug-containing liposomes, or by using liposomes wherein the drugs have been combined and incorporated together into liposomes.
The prior art is deficient in formulations and methods for small particle aerosol delivery of aqueous dispersions of liposomes or lipid complexes containing anti-cancer drugs. The present invention fulfills this long-standing need and desire in the art.